Project 3-- Determining biological and viral factors associated with clinical progression of cervical dysplasia in HIV-infected women

摘要 高危人类乳头瘤病毒(HR HPV)是宫颈癌的病原体，有超过 80%的病例集中在低收入和中等收入国家，进一步集中在非洲 肯尼亚和乌干达等国。有预防HPV的疫苗，但世界上只有不到2%的疫苗 目标人群已经收到了它们。这使得数百万女性面临患宫颈癌的风险。我们需要 了解HR HPV如何影响其宿主细胞，如何失调其环境，以及在高共生率地区。 人类乳头状瘤病毒和艾滋病毒的感染与艾滋病毒协同作用，推动妇女癌症的发展和进展。 宫颈癌发生的最大临床风险因素是持续的HR HPV感染。什么时候 HR HPV感染宫颈，它改变了典型的、顺序激活的细胞生长和分化 支持HR HPV感染和促进癌症发展的途径。在艾滋病毒存在的情况下， HR HPV感染的宿主细胞的途径和功能进一步被破坏，导致更快的进展 癌症。我们假设HR HPV感染表现为可预测的细胞基因表达变化 可在宫颈样本、活检组织和外周血液中检测到。对于艾滋病毒的混合感染，我们假设 还可以检测到一个额外的、重叠的增强的或独特的基因表达变化子集。作为一名 总而言之，这些变化可以作为功能生物标记物，前瞻性地识别癌前病变， 在她的艾滋病毒状况的背景下，对妇女未来患宫颈癌的风险进行分层。识别和验证这些 生物标记物是具体目标1的目标。 除了预测癌症风险的细胞生物标记物外，HR HPV的类型和变异也是一个重要的 与宫颈癌诊断相关的发病率和死亡率的预测因子。目前，还缺乏 侵袭性HPV中最常见的HR HPV类型HPV16变异的遗传格局的基础数据 肯尼亚和乌干达的宫颈癌。我们假设特定的HPV16型变异体增加了这个区域的宫颈 癌症风险；产生关于HPV16变种的详细数据是具体目标2的目标。 我们的具体目标是：(1)确定宿主基因表达的差异 在艾滋病毒阳性和艾滋病毒携带者中，宫颈不典型增生和癌前病变的风险。我们将利用 同步采集宫颈拭子和组织、血液，并通过肉眼检查进行临床检查，以量化 宿主基因表达的变化与病理有关。(2)确定在HIV+和HIV-中发现的HPV16变种 女人。我们将研究HPV16变种并进行全基因组测序，以创建详细的图像 人乳头瘤病毒16型基因多态。通过对HR HPV、其宿主细胞和HR HPV的研究 ，我们将确定生物学和病毒学签名指定艾滋病毒+或艾滋病毒-妇女有风险 宫颈癌的发生和发展。这两个目标的研究将在肯尼亚和乌干达进行， 扩大撒哈拉以南非洲研究人员的科学研究技术和未来管道。

Abstract High-risk human papillomaviruses (HR HPVs) are the causative agent for cervical cancer, with more than 80% of cases clustered in low and middle income countries (LMIC), and a further concentration in African countries like Kenya and Uganda. There are preventive vaccines against HPV, but less than 2% of the world’s target population has received them. This leaves millions of women at risk for cervical cancer. We need to understand how HR HPV affects its host cell, dysregulates its environment, and, in regions with high rates of co- infection of HR HPV and HIV, synergizes with HIV to drive cancer development and progression in women. The greatest clinical risk factor for cervical cancer development is a persistent HR HPV infection. When HR HPV infects the cervix, it changes the typical, sequential activation of cellular growth and differentiation pathways both to support the HR HPV infection and to foster cancer development. In the presence of HIV, the pathways and functions of HR HPV infected host cells are further disrupted, leading a more rapid progression to cancer. We hypothesize that HR HPV infections manifest in predictable cellular gene expression changes that are detectable in cervical samples, biopsy tissues, and peripheral blood. With HIV co-infection, we hypothesize an additional, overlapping subset of augmented or unique gene expression changes are also detectable. As a collective, these changes can serve as functional biomarkers to prospectively identify precancerous lesions and, in the context of her HIV status, to stratify a woman’s future cervical cancer risk. Identifying and validating these biomarkers is the goal of Specific Aim 1. In addition to cellular biomarkers that predict cancer risk, the type and variant of HR HPVs is an important predictor of morbidity and mortality associated with a cervical cancer diagnosis. Currently, there is a lack of foundational data on the genetic landscape of variants of HPV 16, the most common HR HPV type in invasive cervical cancers in Kenya and Uganda. We hypothesize that specific HPV 16 variants add to this region’s cervical cancer risk; generating detailed data on HPV 16 variants is the goal of Specific Aim 2. Our specific aims are: (1) Determine differences in host gene expression that prospectively discriminate among HIV+ and HIV- women the risk for cervical dysplasia and precancerous lesions. We will leverage the synchronous collection of cervical swabs and tissue, blood, and a clinical exam by visual inspection to quantify host gene expression changes linked to pathology. (2) Determine the HPV 16 variants found in HIV+ and HIV- women. We will investigate HPV 16 variants and conduct whole genome sequencing to create a detailed picture of HPV 16 genetic polymorphisms. Through investigations of HR HPV, its host cells, and HR HPV in the context of HIV, we will determine the biologic and virologic signatures designating a HIV+ or HIV- woman at risk for cervical cancer development and progression. Studies for both aims will be performed in Kenya and Uganda, expanding scientific research techniques and future pipelines of investigators in Sub-Saharan Africa.